Design and synthesis of 14 alpha-methyl-15-aza-D-homosterols as novel antimycotics.
A novel series of 14 alpha-methyl-15-aza-D-homosterols 3-7 has been synthesized. These compounds display significant antimycotic activity in vitro (MIC = 0.8-3.1 micrograms/mL) that compares quite favorably to the activity observed for fluconazole (MIC = 0.8 micrograms/mL). Azasterols 3 and 4 were active in vivo as reflected in the increased survival time of Candida albicans infected mice. The antimycotic activity of 3-7 is hypothesized to be a consequence of the inhibition of fungal 14,15-sterol reductase.
Dolle
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Department of Medicinal Chemistry, Smith Kline & French Research Limited, Welwyn, Hertfordshire, U.K.
Allaudeen
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Kruse
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D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis*; D002177:Candidiasis / Q000188:drug therapy; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015195:Drug Design; D051379:Mice; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D013261:Sterols / Q000138:chemical synthesis* / Q000494:pharmacology
D000935:Antifungal Agents; D013261:Sterols; D010088:Oxidoreductases; C022672:delta(14)-sterol reductase; D009247:NADH, NADPH Oxidoreductases